Axitinib (AXT) is a second-generation tyrosine kinase inhibitor widely used in advanced renal cell carcinoma and currently explored in light-modulated therapies due to its E/Z photoisomerizable scaffold. Despite its clinical relevance and UVA absorption, the photobiological consequences of its light-induced structural rearrangements remain largely unexplored. Here, we elucidate the mechanistic basis of AXT phototoxicity by integrating photophysical characterization with cellular studies while distinguishing the roles of its (E)- and (Z)-isomers. Steady-state photolysis reveals that (E)-AXT undergoes photodegradation in aqueous media but preferentially isomerizes to (Z)-AXT in lipophilic environments, which is accelerated in the presence of human serum albumin (HSA). Conversely, (Z)-AXT displays medium-dependent photostability, being stabilized by HSA and reverting to the (E)-isomer in aqueous solution. Spectroscopic studies, including laser flash photolysis, support a mechanism involving tautomerization through excited-state intramolecular proton transfer and transient radical intermediates, consistent with predominant Type I photosensitization. Notably, (Z)-AXT is favored in lipophilic and protein-rich environments, likely through intramolecular hydrogen-bond stabilization of its 2H-tautomer. Cellular studies in keratinocytes revealed two complementary phototoxic pathways: photoinduced conversion of cytotoxic (Z)-AXT from (E)-AXT and the intrinsic phototoxicity of (Z)-AXT under irradiation. Although both isomers cause similar protein oxidation, (Z)-AXT is the main contributor due to its higher stability with HSA. While alkaline comet assays detected no direct DNA strand breaks, γ-H2AX immunostaining revealed light-induced DNA double-strand breaks. Overall, these findings identify (Z)-AXT as a previously unrecognized phototoxic species and establish a framework linking isomerization, microenvironmental stabilization, and Type I photosensitization in kinase inhibitors.

Solar-assisted gaseous CO2 hydrogenation to CH4 is a potential strategy for favoring the transition to net zero emissions. Here, we report the development of a series of efficient metal-organic frameworks with MIL-101(Cr or Fe) topology decorated with RuOx nanoparticles (ca. 0.2-2 wt %) as heterogeneous photocatalysts for the selective methanation of CO2 by H2 under simulated sunlight irradiation. The activity of RuOx(1 wt %)@MIL-101(Cr) is between 3 and 50 times higher than related MOF-based photocatalysts under similar reaction conditions. Among the different photocatalysts, the optimized RuOx(2 wt %)@MIL-101(Cr) photocatalyst showed 98.1% CO2 conversion with 98.8% CH4 selectivity reaching a production rate of 7.85 mmol g-1 h-1 with 720 mW cm-2 at 200 °C. Further, this photocatalyst exhibited a record apparent quantum yield of 9.2% at 600 nm and 200 °C after subtracting thermal activity contribution compared to any previous MOF- or other heterogeneous-based photocatalyst reported so far. The photocatalyst retained its activity and integrity upon reuse for about 110 h. Transient photocurrent, electrochemical impedance, photoluminescence, and laser flash photolysis spectroscopies together with additional photocatalytic experiments suggest the occurrance of dual photochemical and photothermal reaction pathways. The photocatalytic CO2 methanation reaction mechanism was further investigated using operando Fourier transform infrared spectroscopy.

Dasatinib (DAS) is an anticancer drug employed in the treatment of certain hematological malignancies. Although DAS has been mainly developed for oral administration, it has recently garnered attention for its possible topical application. The use of topical drugs can cause photosensitivity, which is not listed as an adverse reaction for DAS. Since DAS absorbs UVA, it could potentially induce photosensitivity reactions and lead to oxidative damage to cellular targets. This study aims to investigate whether DAS exhibits phototoxic reactions on primary cellular targets in both solution and artificial skin, mimicking topical drug administration. It also examines the potential generation of highly reactive intermediates like organic radicals and ROS, which could trigger photosensitivity reactions. Upon DAS irradiation in the UVA region, the first transient species detected was the diradicaloid triplet excited state (3DAS∗) with an absorption maximum of around 490 nm, which was quenched by oxygen to produce singlet oxygen. Quenching experiments with linoleic acid and 3-methylindole indicated that radical-mediated (Type I) photosensitized damage to lipids and proteins is possible. However, the lack of triplet quenching with guanosine suggests that the Type II mechanism also plays a role in the photooxidation of biomolecules. Accordingly, the neutral red uptake phototoxicity test (photoirritation factor of 5) and the comet assay, revealed that this drug is photo(geno)toxic to cells. Moreover, investigations on lipid photoperoxidation, and protein and DNA photooxidation strongly support that different cellular compartments are potential targets for DAS-induced phototoxicity. Regarding its potential application in topical dermatological formulations, an O/W emulsion of DAS was prepared and tested in reconstructed human epidermis, and a significant phototoxicity was also demonstrated. Fortunately, this undesired side effect disappeared upon formulation of DAS along with a sunscreen. Thus, for topical treatments, the photosensitivity reactions induced by DAS can be prevented by using formulations including appropriate UVA filters.

Solar-assisted CO2 conversion into fuels and chemical products involves a range of technologies aimed at driving industrial decarbonization methods. In this work, we report on the development of a series of multifunctional metal-organic frameworks (MOFs) based on nitro- or amino-functionalized UiO-66(M) (M: Zr or Zr/Ti) supported RuOx NPs as photocatalysts, having different energy band level diagrams, for CO2 hydrogenation under simulated concentrated sunlight irradiation. RuOx(1 wt %; 2.2 +/- 0.9 nm)@UiO-66(Zr/Ti)-NO2 was found to be a reusable photocatalyst, to be selective for CO2 methanation (5.03 mmol g(-1) after 22 h;, apparent quantum yield at 350, 400, and 600 nm of 1.67, 0.25, and 0.01%, respectively), and to show about 3-6 times activity compared with previous investigations. The photocatalysts were characterized by advanced spectroscopic techniques like femto- and nanosecond transient absorption, spin electron resonance, and photoluminescence spectroscopies together with (photo)electrochemical measurements. The photocatalytic CO2 methanation mechanism was assessed by operando FTIR spectroscopy. The results indicate that the most active photocatalyst operates under a dual photochemical and photothermal mechanism. This investigation shows the potential of multifunctional MOFs as photocatalysts for solar-driven CO2 recycling.

The photocleavage of homodimeric quinone oxetanes evolves through a non-adiabatic process, the opposite of what has been observed with heterodimeric oxetanes. This is explained by ultrafast transient absorption spectroscopy and quantum chemistry.

The photobiological damage that certain drugs or their metabolites can photosensitize in proteins is generally associated with the nature of the excited species that are generated upon interaction with UVA light. In this regard, the photoinduced damage of the anticancer drug gefitinib (GFT) and its two main photoactive metabolites GFT-M1 and GFT-M2 in cellular milieu was recently investigated. With this background, the photophysical properties of both the drug and its metabolites have now been studied in the presence of the two main transport proteins of human plasma, i.e., serum albumin (HSA) and α1-acid glycoprotein (HAG) upon UVA light excitation. In general, the observed photobehavior was strongly affected by the confined environment provided by the protein. Thus, GFT-M1 (which exhibits the highest phototoxicity) showed the highest fluorescence yield arising from long-lived HSA-bound phenolate-like excited species. Conversely, locally excited (LE) states were formed within HAG, resulting in lower fluorescence yields. The reserve was true for GFT-M2, which despite being also a phenol, led mainly to formation of LE states within HSA, and phenolate-like species (with a minor contribution of LE) inside HAG. Finally, the parent drug GFT, which is known to form LE states within HSA, exhibited a parallel behavior in the two proteins. In addition, determination of the association constants by both absorption and emission spectroscopy revealed that the two metabolites bind stronger to HSA than the parent drug, whereas smaller differences were observed for HAG. This was further confirmed by studying the competing interactions between GFT or its metabolites with the two proteins using fluorescence measurements. These above experimental findings were satisfactorily correlated with the results obtained by means of molecular dynamics (MD) simulations, which revealed the high affinity binding sites, the strength of interactions and the involved amino acid residues. In general, the differences observed in the photobehavior of the drug and its two photoactive metabolites in protein media are consistent with their relative photosensitizing potentials.

Gefitinib (GFT) is a selective epidermal growth factor receptor (EGFR) inhibitor clinically used for the treatment of patients with non-small cell lung cancer. Bioactivation by mainly Phase I hepatic metabolism leads to chemically reactive metabolites such as O-Demethyl gefitinib (DMT-GFT), 4-Defluoro-4-hydroxy gefitinib (DF-GFT), and O-Demorpholinopropyl gefitinib (DMOR-GFT), which display an enhanced UV-light absorption. In this context, the aim of the present study is to investigate the capability of gefitinib metabolites to induce photosensitivity disorders and to elucidate the involved mechanisms. According to the neutral red uptake (NRU) phototoxicity test, only DF-GFT metabolite can be considered non-phototoxic to cells with a photoirritation factor (PIF) close to 1. Moreover, DMOR-GFT is markedly more phototoxic than the parent drug (PIF = 48), whereas DMT-GFT is much less phototoxic (PIF = 7). Using the thiobarbituric acid reactive substances (TBARS) method as an indicator of lipid photoperoxidation, only DMOR-GFT has demonstrated the ability to photosensitize this process, resulting in a significant amount of TBARS (similar to ketoprofen, which was used as the positive control). Protein photooxidation monitored by 2,4-dinitrophenylhydrazine (DNPH) derivatization method is mainly mediated by GFT and, to a lesser extent, by DMOR-GFT; in contrast, protein oxidation associated with DMT-GFT is nearly negligible. Interestingly, the damage to cellular DNA as revealed by the comet assay, indicates that DMT-GFT has the highest photogenotoxic potential; moreover, the DNA damage induced by this metabolite is hardly repaired by the cells after a time recovery of 18 h. This could ultimately result in mutagenic and carcinogenic effects. These results could aid oncologists when prescribing TKIs to cancer patients and, thus, establish the conditions of use and recommend photoprotection guidelines.

Metal-organic frameworks (MOFs) are attracting increasing interests as photocatalysts for solar-driven hydrogen production from water. This paper reports on a comparative study of using either acetic acid (AA) or trifluoroacetic acid (TFA) as the representative UiO-66 organic modulators for synthesizing visible light responsive UiO-66(Zr)-X (X: NH2 or NO2) photocatalysts for water splitting. The results show that photocatalytic hydrogen generation from a water/methanol mixture can be improved by varying the nature and amount of the modulator employed to prepare the different UiO-66(Zr)-X (X: NH2 or NO2) solid derivatives. UiO-66(Zr)-NH2 was the most active photocatalyst, followed by UiO-66(Zr)-NO2, both prepared with 12 equivalents of AA with respect to the organic ligand. This UiO-66(Zr)-NH2 solid was more active than the parent MOF in photocatalytic overall water splitting (OWS) (H2 and O2 production of 450 and 160 µmol·g−1, respectively, in 5 h; apparent quantum yield (AQY) at 400 nm of 0.06

As there is an urgent need to produce solar fuels from CO2, we here report on the development of a series of multimetallic UiO-66(Zr/Ce/Ti) solids-supported RuOx nanoparticles as photocatalysts for selective gas phase CO2 methanation by H-2 under simulated sunlight irradiation. The trimetallic UiO-66(Zr/Ce/Ti) based-photocatalyst exhibits higher activity (1,900 mu mol g(-1) of CH4 after 22 h) than analogous mono- [UiO-66(Zr) or UiO-66 (Ce)] and bimetallic [UiO-66(Zr/Ce) or UiO-66(Zr/Ti)] derivatives, as well as higher than previous reports on metal-organic frameworks (MOFs). The experimental evidence on the observed order of photocatalytic activity and insights into the occurrence of a dual photochemical and photothermal mechanism for the most active trimetallic sample were obtained by means of spectroscopic techniques including fluorescence and laser flash photolysis, photoelectrochemical and additional photocatalytic measurements. This study exemplifies the benefits of developing multimetallic MOF-supported metal nanoparticles to achieve high photocatalytic activity for solar-driven gas phase CO2 conversion.

The interaction dynamics between flurbiprofen (FBP) and tryptophan (Trp) has been studied in covalently linked dyads and within human serum albumin (HSA) by means of fluorescence and ultrafast transient absorption spectroscopy. The dyads have proven to be excellent models to investigate photoinduced processes such as energy and/or electron transfer that may occur in proteins and other biological media. Since the relative spatial arrangement of the interacting units may affect the yield and kinetics of the photoinduced processes, two spacers consisting of amino and carboxylic groups separated by a cyclic or a long linear hydrocarbon chain (1 and 2, respectively) have been used to link the (S)- or (R)-FBP with the (S)-Trp moieties. The main feature observed in the dyads was a strong intramolecular quenching of the fluorescence, which was more important for the (S,S)- than for the (R,S)- diastereomer in dyads 1, whereas the reverse was true for dyads 2. This was consistent with the results obtained by simple molecular modelling (PM3). The observed stereodifferentiation in (S,S)-1 and (R,S)-1 arises from the deactivation of (1)Trp*, while in (S,S)-2 and (R,S)-2 it is associated with (FBP)-F-1*. The mechanistic nature of (FBP)-F-1* quenching is ascribed to energy transfer, while for (1)Trp* it is attributed to electron transfer and/or exciplex formation. These results are consistent with those obtained by ultrafast transient absorption spectroscopy, where (FBP)-F-1* was detected as a band with a maximum at ca. 425 nm and a shoulder at similar to 375 nm, whereas Trp did not give rise to any noticeable transient. Interestingly, similar photoprocesses were observed in the dyads and in the supramolecular FBP@HSA complexes. Overall, these results may aid to gain a deeper understanding of the photoinduced processes occurring in protein-bound drugs, which may shed light on the mechanistic pathways involved in photobiological damage.

Photosensitization by drugs is directly related with the excited species and the photoinduced processes arising from interaction with UVA light. In this context, the ability of gefitinib (GFT), a tyrosine kinase inhibitor (TKI) used for the treatment of a variety of cancers, to induce phototoxicity and photooxidation of proteins has recently been demonstrated. In principle, photodamage can be generated not only by a given drug but also by its photoactive metabolites that maintain the relevant chromophore. In the present work, a complete study of O-desmorpholinopropyl gefitinib (GFT-MB) has been performed by means of fluorescence and ultrafast transient absorption spectroscopies, in addition to molecular dynamics (MD) simulations. The photobehavior of the GFT-MB metabolite in solution is similar to that of GFT. However, when the drug or its metabolite are in a constrained environment, i.e. within a protein, their behavior and the photoinduced processes that arise from their interaction with UVA light are completely different. For GFT in complex with human serum albumin (HSA), locally excited (LE) singlet states are mainly formed; these species undergo photoinduced electron transfer with Tyr and Trp. By contrast, since GFT-MB is a phenol, excited state proton transfer (ESPT) to form phenolate-like excited species might become an alternative deactivation pathway. As a matter of fact, the protein-bound metabolite exhibits higher fluorescence yields and longer emission wavelengths and lifetimes than GFT@HSA. Ultrafast transient absorption measurements support direct ESPT deprotonation of LE states (rather than ICT), to form phenolate-like species. This is explained by MD simulations, which reveal a close interaction between the phenolic OH group of GFT-MB and Val116 within site 3 (subdomain IB) of HSA. The reported findings are relevant to understand the photosensitizing properties of TKIs and the role of biotransformation in this type of adverse side effects.

The publication deals with polymeric pA●pT and oligomeric A20●T20 DNA duplexes whose fluorescence is studied by time-correlated single photon counting. It is shown that their emission on the nanosecond timescale is largely dominated by high-energy components peaking at a wavelength shorter than 305 nm. Because of their anisotropy (0.02) and their sensitivity to base stacking, modulated by the duplex size and the ionic strength of the solution, these components are attributed to mixed ππ*/charge transfer excitons. As high-energy long-lived excited states may be responsible for photochemical reactions, their identification via theoretical studies is an important challenge.

Gefitinib (GFT) is a tyrosine kinase inhibitor currently used for the treatment of metastatic non-small cell lung cancer. Although it has been suggested that GFT can be phototoxic, there are no systematic studies on this issue. Here, the photosensitizing potential of GFT has been assessed by means of NRU assays and protein photooxidation. In addition, a thorough photophysical study is presented based on ultrafast transient absorption spectroscopy, fluorescence and laser flash photolysis. Transient species generated after excitation of GFT have been characterized in solution and in biological environments (i.e. HSA and HaCaT cells) to gain insight into the mechanisms involved in photodamage. The photobehavior of GFT was strongly medium-dependent. Excitation of the drug resulted in the formation of locally excited (LE) singlet states (1GFT*), which were found to be the main emissive species in non-polar solvents and also within HSA and HaCaT cells. By contrast, in polar solvents, LE states rapidly evolved (∼1 ps) towards the formation of longer-lived intramolecular charge transfer (ICT) states. The triplet excited state of GFT (3GFT*) can be formed through intersystem crossing from 1GFT* in non-polar solvents and from ICT states in the polar ones, or in the particular case of ethanol, by photosensitization using 2-methoxyacetophenone as an energy donor. In the HSA environment, 3GFT* was hardly detected due to quenching of its LE 1GFT* precursor by Trp through an electron transfer process. Accordingly, HSA photooxidation by GFT was demonstrated using the protein carbonylation method. In summary, a good correlation is established between the photophysical behavior and the photobiological properties of GFT, which provides a mechanistic basis for the observed phototoxicity.

Lapatinib (LAP) is an anticancer drug, which is metabolized to theN- and O-dealkylated products (N-LAP andO-LAP, respectively). In view of the photosensitizing potential of related drugs, a complete experimental and theoretical study has been performed on LAP,N-LAP andO-LAP, both in solution and upon complexation with human serum albumin (HSA). In organic solvents, coplanar locally excited (LE) emissive states are generated; they rapidly evolve towards twisted intramolecular charge-transfer (ICT) states. By contrast, within HSA only LE states are detected. Accordingly, femtosecond transient absorption reveals a very fast switching (ca. 2 ps) from LE (lambda(max)=550 nm) to ICT states (lambda(max)=480 nm) in solution, whereas within HSA the LE species become stabilized and live much longer (up to the ns scale). Interestingly, molecular dynamics simulation studies confirm that the coplanar orientation is preferred for LAP (or to a lesser extentN-LAP) within HSA, explaining the experimental results.

Lapatinib (LAP) is an anticancer drug generally used to treat breast and lung cancer. It exhibits hypersensitivity reactions in addition to dermatological adverse effects and photosensitivity. Moreover, LAP binds to serum proteins and is readily biotransformed in humans, giving rise to several metabolites, such as N- and O-dealkylated products (N-LAP and O-LAP, respectively). In this context, the aim of the present work is to obtain key information on drug@protein complexation, the first step involved in a number of hypersensitivity reactions, by a combination of fluorescence, femtosecond transient absorption spectroscopy and molecular dynamics (MD) simulations. Following this approach, the behavior of LAP and its metabolites has been investigated in the presence of serum proteins, such as albumins and α1-acid glycoproteins (SAs and AGs, respectively) from human and bovine origin. Fluorescence results pointed to a higher affinity of LAP and its metabolites to human proteins; the highest one was found for LAP@HSA. This is associated to the coplanar orientation adopted by the furan and quinazoline rings of LAP, which favors emission from long-lived (up to the ns time-scale) locally-excited (LE) states, disfavoring population of intramolecular charge transfer (ICT) states. Moreover, the highly constrained environment provided by subdomain IB of HSA resulted in a frozen conformation of the ligand, contributing to fluorescence enhancement. Computational studies were clearly in line with the experimental observations, providing valuable insight into the nature of the binding sites and the conformational arrangement of the ligands inside the protein cavities. Besides, a good correlation was found between the calculated binding energies for each ligand@protein complex and the relative affinities observed in competition experiments.

Direct absorption of UVB light by DNA may induce formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone (6-4) photoproducts. The latter arise from the rearrangement of unstable oxetane intermediates, which have also been proposed to be the electron acceptor species in the photoenzymatic repair of this type of DNA damage. In the present work, direct photolysis of oxetanes composed of substituted uracil (Ura) or thymine (Thy) derivatives and benzophenone (BP) have been investigated by means of transient absorption spectroscopy from the femtosecond to the microsecond time-scales. The results showed that photoinduced oxetane cleavage takes place through an adiabatic process leading to the triplet excited BP and the ground state nucleobase. This process was markedly affected by the oxetane regiochemistry (head-to-head, HH, vs. head-to-tail, HT) and by the nucleobase substitution; it was nearly quantitative for all investigated HH-oxetanes while it became strongly influenced by the substitution at positions 1 and 5 for the HT-isomers. The obtained results clearly confirm the generality of the adiabatic photoinduced cleavage of BP/Ura or Thy oxetanes, as well as its dependence on the regiochemistry, supporting the involvement of triplet exciplexes. As a matter of fact, when formation of this species was favored by keeping together the Thy and BP units after splitting by means of a linear linker, a transient absorption at ∼400 nm, ascribed to the exciplex, was detected.

The photoinduced cycloreversion of oxetanes has been thoroughly investigated in connection with the photorepair of the well-known DNA (6-4) photoproducts. In the present work, the direct photolysis of the two regioisomers arising from the irradiation of benzophenone (BP) and 1,3-dimethylthymine (DMT), namely the head-to-head (HH-1) and head-to-tail (HT-1) oxetane adducts, has been investigated by combining ultrafast spectroscopy and theoretical multiconfigurational quantum chemistry analysis. Both the experimental and computational results agree with the involvement of an excited triplet exciplex 3[BPDMT]* for the photoinduced oxetane cleavage to generate 3BP* and DMT through an adiabatic photochemical reaction. The experimental signature of 3[BPDMT]* is the appearance of an absorption band at ca. 400 nm, detected by femtosecond transient absorption spectroscopy. Its formation is markedly regioselective, as it is more efficient and proceeds faster for HH-1 (∼2.8 ps) than for HT-1 (∼6.3 ps). This is in line with the theoretical analysis, which predicts an energy barrier to reach the triplet exciplex for HT-1, in contrast with a less hindered profile for HH-1. Finally, the more favorable adiabatic cycloreversion of HH-1 compared to that of HT-1 is explained by its lower probability to reach the intersystem crossing with the ground state, which would induce a radiationless deactivation process leading either to a starting adduct or to a dissociated BP and DMT.

Benzophenone (BP) is present in a variety of bioactive molecules. This chromophore is able to photosensitize DNA damage, where one of the most relevant BP/ DNA interactions occurs with thymine (Thy). In view of the complex photoreactivity previously observed for dyads containing BP covalently linked to thymidine, the aim of this work is to investigate whether appropriate changes in the nature of the spacer could modulate the intramolecular BP/Thy photoreactivity, resulting in an enhanced selectivity. Accordingly, the photobehavior of a series of dyads derived from BP and Thy, separated by linear linkers of different length, has been investigated by steady-state photolysis, as well as femtosecond and nanosecond transient absorption spectroscopy. Irradiation of the dyads led to photoproducts arising from formal hydrogen abstraction or Paterno-Buchi (PB) photoreaction, with a chemoselectivity that was clearly dependent on the nature of the linking bridge; moreover, the PB process occurred with complete regio- and stereoselectivity. The overall photoreactivity increased with the length of the spacer and correlated well with the rate constants estimated from the BP triplet lifetimes. A reaction mechanism explaining these results is proposed, where the key features are the strain associated with the reactive conformations and the participation of triplet exciplexes.

Four new dyes that derive from borylated arylisoquinolines were prepared, containing a third aryl residue (naphthyl, 4-methoxynaphthyl, pyrenyl or anthryl) that is linked via an additional stereogenic axis. The triaryl cores were synthesized by Suzuki couplings and then transformed into boronic acid esters by employing an Ir(I)-catalyzed reaction. The chromophores show dual emission behavior, where the long-wavelength emission band can reach maxima close to 600 nm in polar solvents. The fluorescence quantum yields of the dyes are generally in the range of 0.2-0.4, reaching in some cases values as high as 0.5-0.6. Laser-flash photolysis provided evidence for the existence of excited triplet states. The dyes form fluoroboronate complexes with fluoride anions, leading to the observation of the quenching of the long-wavelength emission band and ratiometric response by the build-up of a hypsochromically shifted emission signal.

The study concerns the relaxation of electronic excited states of the DNA nucleoside deoxycytidine (dCyd) and its methylated analogue 5-methyldeoxycytidine (5mdCyd), known to be involved in the formation of UV-induced lesions of the genetic code. Due to the existence of four closely lying and potentially coupled excited states, the deactivation pathways in these systems are particularly complex and have not been assessed so far. Here, we provide a complete mechanistic picture of the excited state relaxation of dCyd/5mdCyd in three solvents-water, acetonitrile, and tetrahydrofuran-by combining femtosecond fluorescence experiments, addressing the effect of solvent proticity on the relaxation dynamics of dCyd and 5mdCyd for the first time, and two complementary quantum mechanical approaches (CASPT2/MM and PCM/TD-CAM-B3LYP). The lowest energy ππ* state is responsible for the sub-picosecond lifetime observed for dCyd in all the solvents. In addition, computed excited state absorption and transient IR spectra allow one, for the first time, to assign the tens of picoseconds time constant, reported previously, to a dark state (nOπ*) involving the carbonyl lone pair. A second low-lying dark state, involving the nitrogen lone pair (nNπ*), does significantly participate in the excited state dynamics. The 267 nm excitation of dCyd leads to a non-negligible population of the second bright ππ* state, which affects the dynamics, acting mainly as a "doorway" state for the nOπ* state. The solvent plays a key role governing the interplay between the different excited states; unexpectedly, water favors population of the dark states. In the case of 5mdCyd, an energy barrier present on the main nonradiative decay route explains the 6-fold lengthening of the excited state lifetime compared to that of dCyd, observed for all the examined solvents. Moreover, C5-methylation destabilizes both nOπ* and nNπ* dark states, thus preventing them from being populated.